PROJECT SUMMARY/ABSTRACT The NCI-designated Dana-Farber/Harvard Cancer Center (DF/HCC) includes the Dana-Farber Cancer Institute (DFCI)/Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH) and the Beth Israel Deaconess Medical Center (BIDMC), which together comprise a Lead Academic Organization (LAO) in the integrated NCI Experimental Therapeutics Clinical Trials Network (ETCTN). Under the auspices of a UM1 Cooperative Agreement, the DF/HCC LAO has participated in 15 NCI-CTEP project teams, with leadership roles on 6 teams, led 20 ETCTN trials and participated in 43 studies, with an average of 102 enrollments per year over the last 5 years. Our LAO utilizes a multiple PD/PI structure and includes (1) a core of translational investigators with expertise in biomarker development for signal transduction, cell cycle, DNA repair and immuno-oncology agents, as well as proficiency in liquid biopsy analyses, computational biology and beside- to-bench cell line, organoid and PDX model development; (2) investigators who conduct Phase 1 and basket studies, as well as eight lead disease-focused investigators who work with DF/HCC Program and SPORE leaders to conduct disease-specific ETCTN trials; (3) representatives of DF/HCC interventional radiology, research pathology and biostatistics; and (4) leaders who direct regulatory oversight, a robust mentoring program for early career clinical and translational investigators and outreach activities designed to increase the enrollment of underserved populations in ETCTN trials. Through continued participation in NCI Project Teams and the leveraging of DF/HCC translational science, DF/HCC investigators will develop letters of intent and statistically rigorous protocols utilizing CTEP IND agents as monotherapies or in rational combinations that will be efficiently conducted and reported in collaboration with other ETCTN sites. Additionally, our investigators will accrue to ETCTN studies led by other LAOs with the overall goal of at least 30% network participation and 100 enrollments per year. Investigators will utilize both DF/HCC cores and NCI central laboratories to incorporate validated integral and integrated biomarker assays and exploratory biomarkers in trial designs that examine proof-of-principle evidence of therapeutic activity in selected patient populations, proof-of-mechanism evidence of target engagement, as well as signatures of response, pathway adaptation and resistance. The DF/HCC LAO will maintain extensive commitments to the training of early career investigators in developmental therapeutics and to strategic initiatives expected to increase the diversity of the population enrolled to ETCTN trials.